Down's Syndrome as a tumour suppressor

A few weeks ago I blogged about Down's syndrome, and this week about cancer and cancer cytogenetics. I've spotted loads of things I neglected to mention about cancer, but there's one thing I deliberately left for another post, because it's something I'm less familiar with and wanted to read a little about. When discussing cancer cytogenetics one usually thinks of the oncogenic effects of aneuploidy and structural aberrations. Certainly, chromosomal aberrations will upset the finely balanced relative concentrations of gene products, and possibly also expose harmful recessive genes, and are therefore very likely to cause disease. They are not guaranteed to cause cancer, however. Indeed, occasionally, it seems that chromosomal aberrations can have a tumour suppressive effect. In a post on Peter Duesburg's cancer origins hypothesis at Respectful Insolence,^[1] Orac mentioned a review in Cancer Cell about the tumour suppressive effect of aneuploidy.^[2] Unfortunately, I can't get it on Athens, so haven't read beyond the abstract, but I get the impression that it may refer to a tumour suppressive effect of aneuploidy accumulated after transformation (from normal to cancerous cell line) has already occurred.

However, a more established tumour suppressive effect of trisomy is observed in Down's syndrome. The life expectancy for DS is around 40, but has been rising, such that the effect of the trisomy on diseases of old age, such as cancer, can now be observed. The incidence of haematological (leukaemias) and soft tissue cancers is raised in DS, but the incidence of solid tumours is reduced, suggesting that chromosome 21 carries gene(s) with tumour suppressive effects. Further evidence of this comes from the observation of loss of heterozygousity of parts of chromosome 21 in many tumours – for example, caused by monosomy/partial monosomy, or other mistakes of cell division.

Solid tumours have to overcome a hurdle that haematological cancers do not: they need a blood supply to maintain their oxygen and energy sources. The growth of new blood vessels, angiogenesis, requires the cooperation of the cells that line existing blood vessels. Without the ability to stimulate those cells into producing new vessels, the tumour won't get far. Endostatin (a product of collagen XVIII) is one of several inhibitors of angiogenesis, and its average blood serum concentration in DS is elevated (though the variation within groups is huge, which is also interesting). Its chromosomal location? 21q22.3, right next to the Downs Syndrome Critical Region (DSCR).^[3] Its tumour suppressive effect (assuming this is the tumour suppressor) is probably through disruption of vascular endothelial growth factor (VEGF, which stimulates angiogenesis) signalling. Unfortunately, it doesn't look like endostatin works as a cancer treatment.^[4]

References

1. ^  Peter Duesberg, chromosomal chaos, and cancer: An intriguing hypothesis argued poorly
2. ^  Beth A.A. Weaver, Alain D. Silk, Cristina Montagna, Pascal Verdier-Pinard and Don W. Cleveland. 2007. Aneuploidy Acts Both Oncogenically and as a Tumor Suppressor. Cancer Cell 11:25-36. PubMed, Full Text.
3. ^  Todd S Zorick, Zan Mustacchi, Silvia Yumi Bando, Mayana Zatz, Carlos Alberto Moreira-Filho, Björn Olsen and Maria Rita Passos-Bueno. 2001. High serum endostatin levels in Down syndrome: implications for improved treatment and prevention of solid tumours. European Journal of Human Genetics 9:811-814. Full Text.
4. ^  Kulke M H et al. 2006. Phase II study of recombinant human endostatin in patients with advanced neuroendocrine tumors. J. Clin. Oncol. 24:3555-3561.